FR3077984A1 - MULTIUSAGE COMPOSITION OF TORASEMIDE - Google Patents

Abstract

The present invention relates to an aqueous composition comprising torasemide and at least one organic solvent, to a vial or container comprising said composition, and to a kit comprising said vial or container and a device for delivering said composition (for example a syringe ). The invention also relates to a use of at least one organic solvent for increasing the stability and / or antimicrobial properties of a composition comprising torasemide. Finally, the present invention also provides a process for preparing a composition according to the invention.

Description

MULTI-PURPOSE COMPOSITION OF TORASEMIDE

Technical area

The present invention relates to an aqueous composition comprising torasemide and at least one organic solvent, to a bottle or container comprising said composition and to a kit comprising said bottle or container and a system for administering the composition (for example a syringe ).

The invention also relates to the use of at least one organic solvent for increasing the stability and / or the antimicrobial properties of a composition comprising torasemide.

Finally, the present invention also relates to a process for preparing the composition according to the invention.

State of the art

Torasemide or torsemide (1-lsopropyl-3 - [(4-m-toluidino-3pyridyl) sulfonyl] urea is a known active ingredient with strong diuretic action and is used to treat edema associated with heart failure , kidney disease and hypertension treatment, human and veterinary therapy.

Torasemide (C16H20N4O3S, M = 348.4 g.mol · ¹ , CAS: 56211-40-6) has the following formula:

Formula I

It is marketed in particular under the brands Demadex®, Diuver®, Dytor®, Examide® and Upcard®.

The diseases for which a treatment comprising torasemide is recommended are chronic diseases which generally require daily treatment.

Recent studies ([1]) have recommended using torasemide for a better diuretic effect. Thus, interest in torasemide is growing in the treatment of heart conditions in particular. Despite these encouraging results, torasemide has a low (or narrow) therapeutic range, which means that any change in its concentration in the body, even small or moderate, can eventually lead to potentially serious side effects. It is therefore important to be able to dispense the required dose.

An ionic imbalance in humans or treated animals is observed with chronic treatment. This imbalance leads to other side effects such as a drop in blood pressure or an increase in aldosterone and creatinine.

To date, furosemide (CAS: 54-31-9) is the standard treatment. It is usually administered orally or intravenously. Recently, breakable tablets based on torasemide have been marketed to address the problem of narrow therapeutic range and dose adjustment according to the weight of humans or animals.

However, this solution does not allow the dose to be adjusted taking into account the whole range of weights available.

Furthermore, the solubility of torasemide depends on the pH of the solution. The stability of the torasemide in solution is also a function of the additives and excipients used in the composition. Torasemide is therefore not soluble at a pH between 2 and 7 approximately (Figure 1).

Torasemide is thus known for its low stability in an aqueous medium. In the state of the art, single-use injectable alkaline solutions based on torasemide are known. Document US 4,861,786 ([2]) in particular describes an injectable alkaline composition of torasemide comprising a physiologically compatible buffer with a pH value of between 9.3 and 9.9 and from 5 to 20% of an organic solvent, said organic solvent being chosen from the group comprising polyethylene glycols (having a molecular weight between 100 and 1500 g.mol · ¹ ), polypropylene glycols (having a molecular weight between 50 and 1000 g.mol · ¹ ), glycerol , propylene glycol, ethanol and propanol. These compositions comprise from 2 to 40 mg.ml · ¹ of torasemide. For reasons of stability, and in particular the appearance of crystals, the pH must be between 9.3 and 9.9, and the percentage of solvents must be less than 20%.

The injectable alkaline torasemide compositions of the state of the art, thus have neither sufficient stability nor an antimicrobial effect guaranteeing their good preservation. In addition, their properties do not allow multiple use (or multi-use), namely repeated use of the same composition over a period of time ranging from several hours to several days.

The known compositions also do not provide a composition which, in addition to increased stability and an antimicrobial effect, offers greater freedom to modulate the doses during administration.

There is therefore a real need for a multi-use aqueous composition, which can be administered orally or parenterally, overcoming these defects, drawbacks and obstacles of the prior art. There is also a need for a bottle or container comprising such compositions making it possible to control the dosage in humans or animals extremely precisely, to reduce costs and thus to improve treatment overall.

Statement of the invention

It is to the credit of the Applicant to have developed torasemide compositions comprising at least one organic solvent at a mass percentage greater than or equal to 30%. Not only is the physical, chemical and / or antimicrobial stability of the composition improved, but it is improved over extended pH ranges, namely between 7.5 and 10, preferably between 8 and 9.9 and even more preferably between 9 and 9.9. Thus, the compositions according to the invention are stable over a period of at least 24 months, preferably 36 months at a storage temperature between 25 and 30 ° C. The improvement of these properties makes the composition suitable for multiple use (or multi-use), namely repeated use of the same composition over a period of time ranging from several hours to several days.

The compositions according to the invention also have an antimicrobial preservation efficacy in accordance with the American and European pharmacopoeias.

Thus, not only is the stability improved, but it is improved over a wide pH range and the composition also benefits from an antimicrobial effect. The latter allows for example to save an antimicrobial preservative in the composition of torasemide.

The invention thus relates to an aqueous composition comprising torasemide and at least one organic solvent, characterized in that the mass concentration of organic solvent can be greater than or equal to 30% relative to the total mass of the composition, preferably greater than or equal to 35% and even more preferably greater than or equal to 40%. Preferably, the concentration of organic solvent can be less than or equal to 70%.

The term "aqueous composition" means a composition comprising water. In the context of the invention, an aqueous composition comprises at least water, an organic solvent and torasemide.

Advantageously, the mass concentration of torasemide can be between 0.01% and 5% relative to the total mass of the composition, preferably between 0.1 and 3% and even more preferably between 0.1 and 2% . The mass concentration of torasemide expressed in mg.ml · ¹ can be between 0.1 and 50 mg.ml · ¹ , preferably between 1 and 30 mg.ml · ¹ and even more preferably between and 20 mg.ml ' ¹ . The mass concentration of torasemide can for example be 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15 or 20 mg.ml ' ¹ . Advantageously, the compositions according to the invention are free from impurities. In the context of the invention, the term "impurities" means particles resulting from the degradation of torasemide, or from the precipitation of torasemide in the form of crystals, molecules of the aldehyde or even ketone type. Preferably, the total concentration of unknown or known impurities, such impurities A and B (European Pharmacopoeia) or impurities A and E (according to the USP) can be less than 5%. The compositions according to the invention can be in the form of clear solutions. In the context of the invention, the term “clear” means a solution which does not contain visible particles according to the monograph of the European Pharmacopoeia.

Advantageously, the at least one organic solvent can be chosen from the group comprising alcohols derived from propane. For example, the organic solvent can be chosen from the group comprising, propylene glycol (also called propane-1,2-diol or PG), glycerol (also called 1,2,3-propanetriol), propan-1, 3-diol (also called PDO), propanol (also called propan-1-ol), isopropanol (also called propan-2ol) and their mixtures. Preferably, the organic solvent can be chosen from the group comprising glycerol and propylene glycol.

Advantageously, the compositions according to the invention may also comprise a physiologically compatible buffer or an alkalizing agent. They can for example be chosen from the group comprising tromethamine (TRIS), triethanolamine, diethanolamine, monoethanolamine, sodium hydroxide, potassium hydroxide, ammonium hydroxide and meglumine. The mass concentration of buffer or basifying agent can be between 1 and 5% relative to the total mass of the composition, preferably between 1 and 2%.

Advantageously, the composition according to the invention may also comprise an agent making it possible to adjust the viscosity (or thickener). Such an agent making it possible to adjust the viscosity may for example be a hydrophilic synthetic polymer of acrylic acid (carbomer), a polysaccharide (cellulose derivatives, chitosans, starches or alginates), a gum, polyvinylpovidone, a poloxamer (pluronic), hydrophilic silica or else a poly (meth) acrylate. The carbomer can be chosen from the group comprising the 2-propenoic acid homopolymer such as, for example, Carbopol 971NF, 974, 934P or 941. The polysaccharide can be chosen from the group comprising starch and its derivatives, derivatives cellulose such as for example hydroxyethylcellulose (HEC), ethylcellulose (EC), carboxymethylcellulose (CMC) and hydroxypropylcellulose (HPC), chitosan derivatives such as for example deacetylated chitin, glucosamine copolymers and of N-acetylglucosamine with different degrees of acetylation and having a molecular weight ranging from 10,000 to 1,000,000. The gums can be chosen from the group comprising xanthan gum and guar gum (galactomannan). The term "derivative" means a conjugate base, a salt, ether, ester or more generally, a compound which is derived from a similar compound by a chemical reaction. The mass concentration of agent allowing the viscosity to be adjusted can be between 0.01 and 10% relative to the total mass of the composition, preferably between 0.1 and 5% and even more preferably between 0.1 and 2%.

Advantageously, the viscosity of the compositions according to the invention can be between 0.001 and 5 Pa.s. Such a viscosity makes it possible to obtain an optimal distribution of the active principle during the administration of the composition.

Advantageously, the composition according to the invention may also comprise an agent making it possible to adjust the osmolarity of the composition. Such an agent can for example be chosen from sugar (glucoses), NaCI or KCI.

Advantageously, the composition according to the invention can also comprise a sweetener. The sweetener can be selected from the group consisting of saccharin (sodium), potassium acesulfame, advantame, aspartame, erythritol and isomalt. The mass concentration of sweetener can be between 0.01 and 2% relative to the total weight of the composition. The term "sweetener" or "sweetening agent" within the meaning of the invention, a compound or mixture of compounds having a sweet taste. The addition of this type of compound to the composition increases the palatability of the latter, when the latter is intended to be administered orally, and thus makes it more easily accepted by the subject, in particular when the medicament is intended to the animal.

Advantageously, the composition according to the invention can also comprise any pharmaceutically acceptable excipient. The composition can thus comprise one or more surfactant (s), inorganic compound (s) or isotonic agent (s).

Advantageously, the compositions according to the invention can have a pH of between 7.5 and 10, preferably between 8.0 and 9.9 and even more preferably between 9 and 9.9 or even 9.3 and 9 9. The pH of the compositions can be easily adapted by a person skilled in the art depending on the solubility and the amount of the components of the composition, and in particular depending on the solubility and the amount of torasemide. The pH of the compositions according to the invention can be adjusted using any pharmaceutically acceptable acid or base. The pH can for example be adjusted by means of NaOH, HCl, meglumine (Nmethylglucamine) or even tromethamine.

The improved stability of the compositions according to the invention also has the advantage of allowing greater modulation in the treatments, by reducing the stresses usually associated with torasemide. The compositions according to the invention provide a more suitable solution for each patient, thanks in particular to the possibility of more easily adjusting the dose distributed to all potential body masses. For the first time in torasemide-based treatments, a composition responds to the problem of dose adjustment to weight, for this substance which has a narrow therapeutic margin.

Also for the first time, a torasemide composition is suitable for multiple use (or multi-use) and overcomes the constraints associated with single-use compositions. This results, for example, in a reduction in the quantity of packaging, more flexible constraints of use or an ease of conservation of an already open composition which would have to be reused.

The compositions according to the invention are thus suitable both for chronic treatment (for example in the form of an oral composition) and for emergency treatment (for example in the form of an injectable composition). The volume of liquid administered to humans or animals can be adjusted according to the required therapeutic dose and the subject's body mass.

Advantageously, the compositions according to the invention can be administered by the oral, subcutaneous (SC), intramuscular (IM) or intravenous (IV) route.

According to another aspect, the invention relates to a composition according to the invention for its use as a medicament, in particular in the treatment of clinical signs, including edema and effusion, linked to congestive heart failure, treatment of kidney disease and hypertension.

The invention thus also relates to:

a use of a composition according to the invention for treating clinical signs, including edema and effusion, linked to congestive heart failure, for treating renal diseases and hypertension,

a method for treating clinical signs, including edema and effusion, linked to congestive heart failure, method for treating renal diseases and hypertension, comprising the administration of a composition according to the invention .

The invention also relates to the use of at least one organic solvent, at a mass concentration greater than or equal to 30%, preferably greater than or equal to 35% and even more preferably greater than or equal to 40%, in an aqueous composition comprising torasemide. Preferably, the mass concentration of at least one organic solvent can be less than or equal to 70%. The invention also includes the use of at least one organic solvent, at a mass concentration greater than or equal to 30%, preferably greater than or equal to 35% and even more preferably greater than or equal to 40% to increase the stability. an aqueous composition comprising torasemide and / or imparting antimicrobial properties to said composition; that is to say that said composition is stable for a period of at least 24 months, preferably 36 months, at a temperature between 25 ° C and 40 ° C, preferably 30 ° C. For example, the composition is stable at least 24 months at a temperature of 30 ° C or at least 36 months at a temperature of 25 ° C. In addition, the composition, after opening, due to its physical, chemical and microbiological stability, can be stored for up to 28 days.

The invention also relates to a process for preparing the compositions according to the invention comprising the steps:

(a) introduction of the buffer or the basifying agent in water at room temperature and stirring to obtain the mixture 1, (b) addition of the torasemide to the mixture 1 and stirring to obtain the mixture 2, (c) progressive addition agent allowing the viscosity to be adjusted with stirring to obtain the mixture 3, (d) optionally adding one or more pharmaceutically acceptable excipient (s) and stirring until a clear solution is obtained (mixture 4), (e) adding the at least one organic solvent and stirring until a clear solution is obtained (mixture 5), (f) optionally adjusting the volume with stirring, (g) optionally adjusting the pH , and obtaining the composition according to the invention.

Agitation can be mechanical (magnetic stirrer) and / or performed using a turbine.

According to another aspect, the invention also relates to a bottle or container comprising a composition according to the invention.

Advantageously, the bottle can be provided with a stopper, a reducer or any other opening system facilitating the delivery of the composition. Such a device, into which a syringe or other system for administering the composition is fitted, makes it possible, depending on the graduation, to administer just the necessary dose, effective and suitable for each treatment. Such a device makes it possible to limit microbial contamination during the use of the composition according to the invention, the administration system (i.e. the syringe) not coming into contact with the composition. For example, during accidental contact, the antimicrobial properties of the composition protect it from possible contamination.

Finally, the invention also relates to a kit comprising:

- a bottle or container comprising a composition according to the invention; and

- a composition administration system.

“Composition administration system” is understood to mean any system allowing the composition to be withdrawn from the bottle or container and then administered by the oral route, SC, IM or IV, such as for example a dropper, a stopper dispenser or syringe.

Other advantages may still appear to a person skilled in the art on reading the examples below.

Brief description of the figures

- Figure 1 shows a solubility curve of torasemide (in mg.ml ' ¹ ) as a function of pH.

- Figure 2 shows a cap and a composition administration system (syringe).

- Figure 3 shows two examples of kits according to the invention (left and right) comprising a bottle with a stopper and an administration system (syringe) of the composition and a reducer (center).

EXAMPLES

Example 1: Preparation of a composition according to the invention

Preparation of a mixture 1:

Water and tromethamine (buffer) are introduced at ambient temperature (18-25 ° C.) with stirring using a deflocculating turbine (speed: 200600 RPM, duration: approximately 15 min).

Preparation of a mixture 2:

Torasemide is added to mixture 1, with stirring using a deflocculating turbine (speed: 200-600 RPM, duration: about 15 min).

Preparation of a mixture 3:

The polymer is gradually added to mixture 2, with stirring using a deflocculating turbine and mechanical stirring (speed: 200-600 RPM, duration: about 15 min).

Preparation of a mixture 4:

The rest of the excipients are added (apart from the organic solvent) to mixture 3, while maintaining the agitation until a clear solution is obtained.

Preparation of a mixture 5:

The organic solvent (propylene glycol) is then added to mixture 4, while maintaining the agitation until a clear solution is obtained.

The volume may be adjusted with water with magnetic stirring, for a minimum of 15 min.

The pH may be adjusted to the desired value.

The composition is obtained in the form of a colorless and slightly viscous liquid.

The compositions in Table 1 below are prepared according to the above protocol, with the quantities indicated in the table.

Composition No. Comparative 1 Composition 1 Composition 2 torasemide 0.30% 0.20% 0.20% Tromethamine (TRIS) 1.50% 1.50% meglumine 1.00% PEG 400 10.00% Propylene glycol 40.00% 40.00% Carbopol 971P 0.20% Natrosol 250G Pharm 1.00% Saccharin sodium 0.20% Hydrochloric acid QSP pH 8.0-10 QSP pH 9.3-9.7 QSP pH 9.3-9.7 Water ppi 100% QSP 100% QSP 100% QSP Table 1: composite tions, comparative example and according to the invention.

QSP = sufficient quantity for. Water ppi = water for injection.

Example 2: Optimized stability of the compositions according to the invention

The stability of compositions 1 and 2 was evaluated under accelerated stressful storage conditions: at a temperature of 40 ° C, at a relative humidity rate of 75% and for a period of T = 2 months.

For each of the compositions tested, the level of impurities is measured according to the method corresponding to the active principle, described in the monographs of the European or American pharmacopoeia.

The results are compiled in Table 2 below:

Composition No. Comparative 1 Composition 1 Composition 2 Macroscopic aspect trouble limpid limpid torasemide content (per dosage, 95,105%) 100.30 99.10 100.00 Each unknown impurity (<0.3%) 0.31 0.02 0.01 Total unknown impurities (<1.0%) 0.41 0.07 0.04

Table 2: stability tests of compositions 1 and 2.

By "unknown impurity" is meant impurities, degradation products and chemical impurities classified "B" and "A" in the European Pharmacopoeia and "A" and "E" in the American Pharmacopoeia (USP).

The results obtained demonstrate that the compositions according to the invention are more stable than the compositions of the state of the art. The 10 compositions according to the invention thus comply with the criteria required by the American and European pharmacopoeias in terms of stability.

Example 3 Antimicrobial Properties of the Compositions According to the Invention

The antimicrobial efficacy was assessed according to the European monograph.

The following compositions (A to I according to the invention and CE1 to CE7 counterexamples) were prepared according to the procedure of Example 1.

ingredients Percentage composition (in% m / m) CE1 (0% PG) CE2 (20% PG) A (40% PG) torasemide 0.20 0.20 0.20 tromethamine 1.50 1.50 1.50 carbomer 0.20 0.20 0.20 Propylene glycol 0.00 20.00 40,00 Purified water q.s.p m / m 98.10 78,10 58.10 Total (% w / w) 100.00 100.00 100.00 Antimicrobial preservation efficiency (Ph Eur) NC NC VS S. aureus VS VS vs E. coli VS VS vs Ps. Aeruginosa vs vs vs C. albicans vs vs vs A. brasiliensis NC NC vs

Table 3: Efficacy of antimicrobial conservation of different batches with 0.2% carbomer and with different quantities of propylene glycol. NC = non-compliant, C = compliant.

ingredients Percentage composition (in% m / m) CE3 (0% PG) CE4 (20% PG) B (40% PG) torasemide 0.20 0.20 0.20 tromethamine 1.50 1.50 1.50 Hydroxyethyl cellulose 1.00 1.00 1.00 Propylene glycol 0.00 20.00 40.00 Purified water q.s.p m / m 97.30 77.30 57.30 Total (% w / w) 100.00 100.00 100.00 Antimicrobial preservation efficiency (Ph Eur) NC NC VS S. aureus NC VS vs E. coli VS VS vs Ps. Aeruginosa VS NC vs C. albicans NC VS vs A. brasiliensis NC NC vs

Table 4: Efficacy of antimicrobial conservation of different lots with 1% HEC and with different amounts of propylene glycol. NC = non-compliant, C = compliant.

ingredients Percentage composition (in% m / m) CE5 c (35% PG) D (45% PG) torasemide 0.20 0.20 0.20 tromethamine 1.50 1.50 1.50 Xanthan gum 0.30 0.30 0.30 Propylene glycol 0.00 35,00 45,00 Purified water q.s.p m / m 98,00 63,00 53,00 Total (% w / w) 100.00 100.00 100.00 Antimicrobial preservation efficiency (Ph Eur) NC VS VS S. aureus NC vs vs E. coli VS vs vs Ps. Aeruginosa NC vs vs C. albicans NC vs vs A. brasiliensis NC vs vs Antimicrobial conservation efficacy (USP) NC vs vs S. aureus VS vs vs E. coli VS vs vs Ps. Aeruginosa NC vs vs C. albicans VS vs vs A. brasiliensis vs vs vs

Table 5: Efficacy of antimicrobial preservation of different batches with 0.3% xanthan gum and with different quantities of propylene glycol. NC = non-compliant, C = compliant.

ingredients Percentage composition (in% m / m) EC6 E F G torasemide 0.20 0.20 0.20 0.20 tromethamine 1.50 1.50 1.50 1.50 Propylene glycol / 30,00 45,00 60,00 Carbopol 971P 0.15 0.15 0.15 0.15 Purified water q.s.p m / m q.s.p 100.00 qs 100.00 q.s.p 100.00 q.s.p 100.00 Antimicrobial preservation efficiency (Ph Eur) NC VS VS VS S. aureus VS VS VS VS E. coli VS vs vs vs Ps. Aeruginosa vs vs vs vs C. albicans vs vs vs vs A. brasiliensis NC vs vs vs

Table 6: Evaluation of the antimicrobial efficacy of Propylene Glycol as a function of its content with 0.15% of Carbopol 971 P. They differ from each other by the content of propylene glycol: 0, 30, 45 and 60% m / m . NC = non-compliant, C = compliant.

ingredients Percentage composition (in% m / m) EC7 H I torasemide 0.20 0.20 0.20 tromethamine 1.50 1.50 1.50 Propylene glycol / 45,00 60,00 Xanthan gum 0.20 0.20 0.20 Purified water q.s.p m / m q.s.p 100.00 q.s.p 100.00 q.s.p 100.00 Antimicrobial preservation efficiency (Ph Eur) NC VS VS S. aureus NC VS VS E. coli VS vs vs Ps. Aeruginosa NC vs vs C. albicans NC vs vs A. brasiliensis NC vs vs Table 7: Assessment of th Antimicrobial effectiveness of Propylene Glyco

depending on its content with 0.15% xanthan gum. They differ from each other by the propylene glycol content: 0.45 and 60% m / m. NC = not 5 compliant, C = compliant.

The compositions comprising a content greater than or equal to 30% of propylene glycol have made it possible to obtain an antimicrobial preservation efficiency in accordance with the European pharmacopoeia, said pharmacopoeia having the strictest criteria (tighter tolerance intervals) in terms of antimicrobial preservation efficiency, unlike compositions comprising less than 30% organic solvent (ie propylene glycol).

Claims (14)

1. Aqueous composition comprising torasemide and at least one organic solvent chosen from the group comprising alcohols derived from propane, preferably chosen from propylene glycol, glycerol, propan-1,3-diol, propanol, isopropanol and their mixtures, characterized in that the mass concentration of organic solvent is greater than or equal to 30% relative to the total mass of the composition, preferably greater than or equal to 35% and even more preferably greater than or equal to 40 %. 2. Composition according to claim 1, in which the mass concentration of torasemide is between 0.01% and 5% relative to the total mass of the composition, preferably between 0.1 and 3% and even more preferably between 0.1 and 2%. 3. Composition according to any one of the preceding claims, further comprising a buffer or an basifying agent, preferably chosen from the group comprising tromethamine (TRIS), triethanolamine, diethanolamine, monoethanolamine, sodium hydroxide, potassium hydroxide, ammonium hydroxide and meglumine, the mass concentration in buffer preferably being between 1 and 5% relative to the total mass of the composition. 4. Composition according to any one of the preceding claims, further comprising an agent making it possible to adjust the viscosity, chosen from the group comprising synthetic hydrophilic polymers of acrylic acid, polysaccharides, gums, polyvinylpovidone, poloxamers, hydrophilic silica and poly (meth) acrylates, the mass concentration of agent making it possible to adjust the viscosity preferably being between 0.01 and 10% relative to the total mass of the composition. 5. Composition according to any one of the preceding claims, further comprising a sweetener. 6. Composition according to the preceding claim, in which the viscosity is between 0.001 and 5 Pa.s. 7. Composition according to any one of the preceding claims, further comprising one or more pharmaceutically acceptable excipient (s). 8. Composition according to any one of the preceding claims, in which the pH is between 7.5 and 10, preferably between 8.0 and 9.9 and even more preferably between 9 and 9.9 or even 9.3 and 9.9. 9. Composition according to any one of claims 1 to 8, for its use as a medicament, preferably intended for use in the treatment of clinical signs, including edema and effusion, linked to congestive heart failure, the treatment of kidney disease and hypertension. 10. Use of at least one organic solvent chosen from the group comprising alcohols derived from propane, preferably chosen from propylene glycol, glycerol, propan-1,3-diol, propanol, isopropanol and their mixtures , at a mass concentration greater than or equal to 30%, preferably greater than 35% and even more preferably greater than 40%, in an aqueous composition comprising torasemide. 11. Use of at least one organic solvent chosen from the group comprising alcohols derived from propane, preferably chosen from propylene glycol, glycerol, propan-1,3-diol, propanol, isopropanol and their mixtures , at a mass concentration greater than or equal to 30%, preferably greater than 35% and even more preferably greater than 40%, for increasing the stability of an aqueous composition comprising torasemide and / or conferring antimicrobial properties on said composition. 12. Process for the preparation of a composition according to any one of claims 1 to 9, comprising the steps, optionally under an inert atmosphere, of: (a) introduction of the buffer or the basifying agent in water at room temperature and stirring to obtain the mixture 1, (b) addition of the torasemide to the mixture 1 and stirring to obtain the mixture 2, (c) progressive addition of the agent allowing the viscosity to be adjusted, with stirring, to obtain the mixture 3, (d) optionally, addition of one or more pharmaceutically acceptable excipient (s), and stirring until obtaining d '' a clear solution, to obtain the mixture mixture 4, (e) adding the at least one organic solvent and stirring until obtaining a clear solution, to obtain the mixture 5, (f) optionally, adjusting the volume with stirring, (g) optionally, adjusting the pH, and obtaining the composition according to the invention. 13. Bottle or container comprising a composition according to any one of claims 1 to 9. 14. Kit including: - a bottle or container according to the preceding claim; and - a composition administration system.